Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis.
BACKGROUND
Urinary oxalate is a major risk factor for calcium oxalate stones. Marked hyperoxaluria arises from mutations in 2 separate loci, AGXT and GRHPR, the causes of primary hyperoxaluria (PH) types 1 (PH1) and 2 (PH2), respectively. Studies of null Slc26a6(-/-) mice have shown a phenotype of hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis, leading to the hypothesis that SLC26A6 mutations may cause or modify hyperoxaluria in humans.


METHODS
Cross-sectional case-control.


METHODS
Cases were recruited from the International Primary Hyperoxaluria Registry. Control DNA samples were from a pool of adult subjects who identified themselves as being in good health.


METHODS
PH1, PH2, and non-PH1/PH2 genotypes in cases.


METHODS
Homozygosity or compound heterozygosity for SLC26A6 variants. Functional expression of oxalate transport in Xenopus laevis oocytes.


RESULTS
80 PH1, 6 PH2, 8 non-PH1/PH2, and 96 control samples were available for SLC26A6 screening. A rare variant, c.487C-->T (p.Pro163Ser), was detected solely in 1 non-PH1/PH2 pedigree, but this variant failed to segregate with hyperoxaluria, and functional studies of oxalate transport in Xenopus oocytes showed no transport defect. No other rare variant was identified specifically in non-PH1/PH2. Six additional missense variants were detected in controls and cases. Of these, c.616G-->A (p.Val206Met) was most common (11%) and showed a 30% reduction in oxalate transport. To test p.Val206Met as a potential modifier of hyperoxaluria, we extended screening to PH1 and PH2. Heterozygosity for this variant did not affect plasma or urine oxalate levels in this population.


CONCLUSIONS
We did not have a sufficient number of cases to determine whether homozygosity for p.Val206Met might significantly affect urine oxalate.


CONCLUSIONS
SLC26A6 was effectively ruled out as the disease gene in this non-PH1/PH2 cohort. Taken together, our studies are the first to identify and characterize SLC26A6 variants in patients with hyperoxaluria. Phenotypic and functional analysis excluded a significant effect of identified variants on oxalate excretion.
Monico
Carla G
CG
Mayo Clinic Hyperoxaluria Center, Division of Nephrology and Hypertension, Departments of Internal Medicine and Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA. monico.carla@mayo.edu
Weinstein
Adam
A
Jiang
Zhirong
Z
Rohlinger
Audrey L
AL
Cogal
Andrea G
AG
Bjornson
Beth B
BB
Olson
Julie B
JB
Bergstralh
Eric J
EJ
Milliner
Dawn S
DS
Aronson
Peter S
PS
D000293:Adolescent; D000328:Adult; D002129:Calcium Oxalate / Q000378:metabolism; D016022:Case-Control Studies; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D053040:Nephrolithiasis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D000076988:Sulfate Transporters; D055815:Young Adult
D026901:Membrane Transport Proteins; C439529:SLC26A6 protein, human; D000076988:Sulfate Transporters; D002129:Calcium Oxalate